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WO1992000970A1 - Compose de pyrimidine et sel pharmaceutiquement acceptable de ce compose - Google Patents

Compose de pyrimidine et sel pharmaceutiquement acceptable de ce compose Download PDF

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Publication number
WO1992000970A1
WO1992000970A1 PCT/JP1991/000898 JP9100898W WO9200970A1 WO 1992000970 A1 WO1992000970 A1 WO 1992000970A1 JP 9100898 W JP9100898 W JP 9100898W WO 9200970 A1 WO9200970 A1 WO 9200970A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
pharmaceutically acceptable
cells
present
Prior art date
Application number
PCT/JP1991/000898
Other languages
English (en)
Japanese (ja)
Inventor
Akira Mizuchi
Ken Ikeda
Yuichiro Kokubun
Kazutoshi Horikomi
Tadayuki Sasaki
Akira Awaya
Ikuo Tomino
Masaharu Ishiguro
Takumi Kitahara
Noriaki Kihara
Original Assignee
Mitsui Petrochemical Industries, Limited
Mitsui Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsui Petrochemical Industries, Limited, Mitsui Pharmaceuticals, Inc. filed Critical Mitsui Petrochemical Industries, Limited
Priority to US07/836,283 priority Critical patent/US5358945A/en
Priority to DE69120221T priority patent/DE69120221T2/de
Priority to KR1019920700487A priority patent/KR950007756B1/ko
Priority to EP91911732A priority patent/EP0489925B1/fr
Publication of WO1992000970A1 publication Critical patent/WO1992000970A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel pyrimidine compound or a pharmaceutically acceptable salt thereof, and a novel therapeutic agent for a peripheral nervous system and central nervous system nervous system in animals containing the same as an active ingredient.
  • JP-B-46-23394 discloses the following formula
  • A is C or ie alkylene of up to, or ⁇ Mi amino group also properly is lower alkylene substituted by a lower Ashiruami amino group of C 2 ⁇ s ;
  • M is H, Na, K, be ⁇ 4, Mg, Ca or an organic basic Anmoniumu salts; is n an element of equal value to the valence of M,
  • aminobirimidines represented by the formula have an interesting therapeutic activity, especially an activity as an antidepressant or a psychostimulant in the field of psychosis treatment.
  • Japanese Patent Publication No. 51-22044 discloses that dichloro lower aliphatic carboxylate of 2-isopropylaminopyrimidine, for example, dichloroacetate of 2-isopropylaminopyrimidine is useful as a therapeutic agent for neurological diseases. Can be open It is shown.
  • JP-A-52-100477 JP-B-59-285478 discloses that phosphate of 2-isopropylaminovirimidine is useful as a therapeutic agent for neurological diseases.
  • JP-A-54-157575 discloses a method for producing 2-cyclomethylpyrimidine in high yield, and its working example gives 69% yield of 2-cyclomethylpyrimidine. Specific examples are described.
  • Japanese Patent Application Laid-Open No. 55-393 discloses a method for producing 2-isopropylaminopyrimidine in high yield. Examples thereof include 2-isopropylthiopyrimidine with a yield of 60%. A specific example of obtaining pyrimidine is described.
  • JP-A-55-122768 discloses the following formula:
  • a 4 , A 5 and A 6 each represent H or OH, and at least one of them represents 0H.
  • JP-A-55-145670 discloses the following formula:
  • ', A 5', and Alpha beta ' are each represent H or a halogen atom, a least 1 Wwaha opening Gen atoms of these,
  • 2-isopropylaminohalogeno pyrimidine represented by is useful for treating various neuropathies and muscular dystrophies.
  • Japanese Patent Application Laid-Open No. 55-145671 discloses a method for producing a hydroxy derivative of 2-isopro "Jk minopyrimidine.
  • JP-A-55-151571 discloses that 2-isopropylamino-5-halogenobilimidine is of interest in the treatment of neurological diseases.
  • JP-A-56-10177 discloses that 2-methylsulfonylpyrimidine is subjected to aminolysis with isopropylamine to give 2-isopropylpropylaminopyrimidine in a substantial yield.
  • the c Sho 56-26880 discloses that a method of manufacturing are disclosed, bis 1 (isopropyl grayed Anijin) sulfate, 1, 3, was reacted with 3 Te captured Tokishiburo van with 2-isopropyl ⁇ Mi No Pyrimidine Are disclosed.
  • JP-A-56-90013 discloses muscular dystrophy, myopathy, myopathy, and Z or muscle containing a pyrimidine-substituted derivative or a therapeutically acceptable salt thereof or a metabolite thereof as an active ingredient. Agents for treating neurotransmission disorders have been described. However, the publication only discloses various salts of the active compound, such as orthophosphate of 2-isopropylaminovirimidine.
  • JP-A-61-65873 discloses the following formula:
  • R 1 is H or aralkyl
  • Y is a divalent organic group specified and described in the publication-
  • a 2-piperazino pyrimidine derivative represented by the following formula is used as a paddy field and upland field herbicide.
  • the present inventor has previously provided a novel therapeutic agent for a neurological disease containing a specific pyrimidine derivative or a pharmaceutically acceptable salt thereof (International Publication No. 087/04928, W089 / 01938. Japanese Patent Application No. 1-41729, Japanese Patent Application No. 1-334759). [Problems to be solved by the invention]
  • An object of the present invention is to provide a novel pyrimidine compound and a novel pyrimidine compound. Or to provide a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a therapeutic agent for a neurological disease comprising the above novel compound of the present invention.
  • Still another object of the present invention is to provide a novel therapeutic agent for neurological diseases applicable to disorders of peripheral nerve, bone marrow damage and the like.
  • Still another object of the present invention is to apply a neurological disorder in which an abnormality in the action system and metabolic system of a neurotransmitter is considered to be the primary administration ⁇ to a different central nervous system disorder disease.
  • An object of the present invention is to provide a novel therapeutic agent for neurological diseases.
  • Still another object of the present invention is to provide a novel therapeutic agent for brain diseases having an effect of improving and restoring learning data.
  • Still another object of the present invention is to provide a novel therapeutic or therapeutic agent comprising, as an active ingredient, a totally excellent compound having few side effects such as liver injury and having a pharmacological action suitable for treating a neurological disease or a brain disease.
  • a novel therapeutic or therapeutic agent comprising, as an active ingredient, a totally excellent compound having few side effects such as liver injury and having a pharmacological action suitable for treating a neurological disease or a brain disease.
  • R 2 'and R 3 ' are lower alkyl groups
  • R 4 ' is a hydrogen atom, lower alkyl group, Xnyl group or benzyl group
  • Y is —N (wherein an elementary atom or lower ⁇ ⁇ ⁇ 3 R 2 is water
  • a kill group, R 3 is a lower acyl group,-
  • R 4 is a hydrogen atom, a trifluoromethyl group, a hydroxyl group, Ano group, formyl group, lower acyl group, lower alkoxycarbonyl group or fluorosulfonyl group),
  • a compound of the above formula (I) or a pharmaceutically acceptable salt thereof is contained as an active ingredient.
  • the present invention provides a therapeutic agent for depressed sickness, which is characterized in that:
  • the compound of the above formula (I) of the present invention can be prepared by a method known per se, in particular, a method described in JP-A-61-140568 and JP-A-61-87627 and an intermediate obtained by these methods. It can be produced by a method known per se (for example, reductive removal of a protecting group). In Examples 1 to 3 described later, the production methods of each compound are described in detail.
  • reaction of Reaction Scheme 1 is carried out in a solvent such as toluene, dioxane, pyridine or water as necessary. It is suitably carried out at a temperature of from 20 to 150 ° C. in the presence of a basic compound.
  • a basic compound for example, organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine and inorganic bases such as sodium carbonate and carbonated lime are suitably used.
  • X is Y
  • a compound that is -N NCR 5 is, for example, 2,4-dic
  • reaction scheme 2 When it is intended to produce a compound of formula (I), the compound can be produced by the method shown in the following reaction scheme 2.
  • the reaction for synthesizing the compound (W) of Reaction Scheme 2 is carried out in a solvent such as isopropanol, n-butanol, n-pentanol, or isopenanol, if necessary, in the presence of a basic compound. It can be suitably carried out at a temperature of 60 to 200.
  • a basic compound for example, organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium carbonate and potassium carbonate are preferably used.
  • the reaction for synthesizing the compound (V) can be suitably carried out without solvent or in a solvent such as methylene chloride, chloroform, ethylene dichloride or toluene at a temperature of 0 ° C to 100 ° C.
  • a solvent such as methylene chloride, chloroform, ethylene dichloride or toluene at a temperature of 0 ° C to 100 ° C.
  • the compound of the above formula (I) of the present invention was found to be useful as a therapeutic drug for neurological diseases.
  • the compound of formula (I) is usually used in the form of a pharmaceutical composition and is administered by various routes such as oral, subcutaneous, intramuscular, intravenous, intranasal, transdermal and rectal routes.
  • the present invention includes a pharmaceutical composition containing a compound of the general formula (I) or a pharmaceutically acceptable salt thereof as a pharmaceutically acceptable carrier and an active ingredient.
  • Acceptable salts include, for example, acid addition salts as well as quaternary ammonium (or ammonium) salts.
  • Examples of pharmaceutically acceptable salts of compound (I) of the present invention include hydrochloride, hydrobromide sulfate, bisulfate, phosphate, acid phosphate, acetate , Maleate, fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, sugar, methanesulfonate, p-toluenesulfonate, naphthene Salts formed from acids which form non-toxic acid addition salts having a pharmaceutically acceptable anion such as lensulfonic acid salt, or hydrates thereof, and quaternary ammonium (or amide) salts Or their hydrates.
  • composition of the present invention includes, for example, tablets, capsules, powders, granules, troches, cassiers, elixirs, emulsions and milks. It can be in the form of solutions, syrups, suspensions, aerosols, ointments, sterile injectable solutions, molded cataplasms, soft and hard gelatin capsules, suppositories and sterile packaged powders.
  • Examples of pharmaceutically acceptable carriers include lactose, glucose, sucrose, sorbitol, mannitol, corn flour, microcrystalline cellulose, gum arabic, calcium calcium phosphate, alginate, cay Calcium acid, microcrystalline cellulose, polyvinylpyrrolidone, gum tragacanth, gelatin, syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert Bolima — kind, water or mineral oil.
  • any of the solid or liquid compositions may contain, in addition to the carriers described above, fillers, binders, lubricants, wetting agents, disintegrants, emulsions and suspensions, preservatives, sweeteners, and fragrances. May be included.
  • the composition may also be disposed of such that the active ingredient is released rapidly, gunshot or delayed after administration to the patient.
  • the compounds of formula (I) are mixed with carriers or diluents to give tablets, capsules and the like.
  • the active ingredient is dissolved in 10% dextrose in water, isotonic saline, sterile water or similar liquids, and injected intravenously or by intramuscular injection Sealed in a vial or amble to be administered by
  • dissolution aids, local anesthetics, preservatives and buffers can also be included in the vehicle.
  • the composition can be lyophilized after it has been poured into vials or ambles.
  • Other formulations for parenteral administration include, for example, transdermally administered formulations such as softeners and poultices. In this case, a molded pub / tape agent is advantageous.
  • compositions generally contain between 0.1 and 2000 mg, preferably between 0.5 and 10 mg of active ingredient per unit dosage form.
  • the compounds of formula (I) are effective over a wide H content range.
  • daily dosages usually range from 0.03 mg Z kg to 100 mg Z kg.
  • the actual amount of compound to be administered will be determined by a physician, depending on the compound to be administered and on the age, weight, response, severity of the symptoms, the route of administration, etc., of the individual patient. Accordingly, the above dosage ranges do not limit the scope of the invention.
  • the preferred number of doses per day is usually 1 to 6 times, preferably 1 to 4 times.
  • the compound of the formula (I) is an effective therapeutic agent for peripheral neuropathy and central nervous system disorder by itself, but it can also be administered in combination with one or more other similar drugs if necessary. Wear.
  • additional drugs include ganglions Species, Mecobalamin, and Isaxonine.
  • Tablets containing the active ingredient lOm are prepared as follows.
  • Total 120mg Active ingredient, bush flour and microcrystalline cellulose are thoroughly mixed through an 80 mesh sieve.
  • the resulting powder is mixed with a polyvinylpyrrolidone solution, granulated, and passed through an 18 mesh sieve.
  • the granules so produced are dried at 50 to 60 e C, it is granulated by sieving again 18 mesh.
  • the sieved force of 80 mesh is added to the granules, calcium lipoxymethylcellulose, magnesium stearate and talc, and mixed, and tablets are weighed to produce 120 mg each using a tablet machine.
  • Tablets containing 2 OOmg of active ingredient are prepared as follows.
  • Total 300mg Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The resulting powder is compression molded to produce tablets weighing 300 mg.
  • Capsules containing 1 OOmg of active ingredient are prepared as follows. One
  • Total 150mg Combine the above ingredients, pass through 80 mesh sieve, complete Mix thoroughly. Fill the capsules with 150 mg of the obtained powder.
  • a ready-to-dissolve injection in a vial containing 5 mg of the active ingredient is produced as follows.
  • Injections in ambles containing 50 mg of the active ingredient are prepared as follows.
  • An adhesive patch preparation containing 17.5 mg of the active ingredient is produced as follows.
  • 2 parts of glycerin diglycidyl ether are dissolved in 10 parts of water while heating.
  • Voljelen glycol (grade 400) 10 parts, water 10 parts, active ingredient One part is stirred and dissolved.
  • the aqueous solution of glycerin diglycidyl ether and the aqueous solution containing the active component of volyylene glycol are added to the aqueous solution of polyacrylic acid ammonium while stirring the aqueous solution of the drug-containing hydrogel to form a flexible plastic film.
  • the composition was applied so that the amount of the component was 0.5 mg per square meter, and the surface was covered with a coating, and the surface was covered with 35 square centimeters (cut to form a preparation.
  • An adhesive patch containing 10 mg of the active ingredient is produced as follows. Eleven
  • the compound of the present invention of the above formula (I) is applied to neural cells.
  • Biological activity was tested in vitro.
  • Neural cells include the established mouse neuroblastoma neuro-2a strain (Dainippon Pharmaceutical) and the NS-20Y strain.
  • the neurons were expanded to exponential growth in a 5% CO 2 incubator at 37 and then cultured with the compounds of the invention for a period of time.
  • the compound of the present invention was significantly and significantly different from the control culture, and also compared with the control drug isaxonine (the compound described in JP-B-59-28548). It has been found that it has the same or higher activity of promoting neuronal cell proliferation, neurite formation and neurite outgrowth.
  • a rat was prepared by crushing the sciatic nerve, a peripheral neuropathy model, and the effect of the compound of the present invention was tested.
  • the compounds of the present invention may have a promoting effect on the distance between the toes of the toes, the weight of the extensor extensor muscle and the weight of the soleus muscle to normal values. It was revealed.
  • a central nervous system disorder model was prepared in rats, mice and the like, and the efficacy of the compound of the present invention was tested. That is, the substantia nigra dopamine cells of rat I ⁇ were chemically destroyed by microinjection of 6-h droxydopamine, resulting in motor impairment. Two weeks later, fetal brain dopamine cells were transplanted into the caudate nucleus on the rupture side of the rat brain to improve motor dysfunction. That is, from the day of transplantation, the compound of the present invention was orally or intraperitoneally administered for two consecutive days for two consecutive days, and its effects on improving dyskinesia and growing transplanted cells were examined. It has been clarified that the compounds of the present invention have a promoting effect on improvement of movement disorders and the like.
  • the compound of the present invention was administered to an animal in which the basal forebrain was destroyed with ibotenic acid or the like, and the amount of acetylcholine infiltrated in each part of the cerebral cortex and the activity of coryneacetyltransferase were determined.
  • the improvement effect by the compound of Example 2 was clarified.
  • mice and rats with neuropathy caused by mercury poisoning were prepared, and the activity of the compound of the present invention was tested.
  • the effects of improving the symptoms, promoting the recovery to a normal state, treating effects, and learning were also examined. Has memory improvement, recovery effects, etc. Rukoto has been shown.
  • the compound of the present invention is useful as an agent for ameliorating and treating various neurological diseases such as peripheral neuropathy and central nervous system dysfunction in mammals, or as an agent for improving learning and memory.
  • various types of neurobees are representative.
  • various peripheral neuropathies with motogenic, sensory and / or objective retarded reflexes including traumatic or inflammatory, radiculopathy of immunological origin, and alcohol and drug-induced Metabolic such as diabetic, and idiopathic peripheral neuropathy.
  • the compounds of the present invention can also be applied to various disease disorders including central nervous system disorders.
  • a 0.05% aqueous solution of methylene blue is added to stain the cells, and the cells are stained under a microscope and visually observed as neurite outgrowth cells (cells having one or more protrusions that are at least twice as long as the major axis of the cells).
  • ⁇ ⁇ ⁇ was calculated, and the ratio to the total cell number was calculated. 5 or more visual fields (more than 2% of the total surface area of the gun) were observed with the left and right guns centered on the mark on the bottom, and the number of cells was counted as 200 or more.
  • mice neuroblastoma cells NS-20Y were similarly cultured on polyorditin-coated dishes, The effect of each drug was investigated. Table 8 shows the results after 24 hours and 48 hours of culture.
  • the therapeutic effect of the compound of the present invention on the sciatic nerve crush rat in a peripheral neuropathy model was used as an index of (1) functional change of the hind limb on the crush side and (2) change in muscle weight as a degeneration and regeneration process of the peripheral nerve. Tested.
  • test drug was selected from the compounds of the present invention and administered orally or intraperitoneally once a day from the same day as the crushing until the 30th day.
  • a control group a group to which 0.9% physiological saline or the like was administered was provided.
  • the rats were anesthetized with chloral hydrate (400 mg / kg. Ip), and the twitch tension was measured according to the method of Kern et al. (J, Neuros ci. Methods, 19, -259 (1987)). . That is, after shaving the hind limb of the rat, an electrode with a pen lip was mounted on the skin of the hind limb to which the cardio cream was applied. The negative electrode was attached to the posterior part of the greater trochanter, the positive electrode was placed 1 cm behind and 1 era dorsal. The rat was fixed in the supine position, and the hind limb on the measurement side was fixed vertically.
  • One end of a silk thread about 20 cm in length is connected to the distal joint of the third toe of the hind limb on the measurement side, and the other end is connected to a tension transducer, and the isotonic contraction of the flexor muscle of the third toe during electrical stimulation is borographed.
  • Electrical stimulation was performed using a square wave with a voltage of 100 V and a duration of 1 rase at a frequency of 2 Hz.
  • the resting tension was 15 to 30 g, and the stimulation was repeated three times at 15-second intervals.
  • the contractile force was expressed as tension g, and the recovery rate (, left, right) of the crush side contractive force was calculated from the measured values of both limbs.
  • the test compound enhanced the recovery of the electrophysiological index, twitch tension, and improved the symptoms as compared to the control.
  • the distance between the toes was determined by measuring the distance between the first and fifth toes of the hind limb according to Hasegawa's method (see Hasegawa, K., Experientia, 34750-751) (1978). The ratio of the distance on the crush side to the distance on the normal side was determined. The distance between the toes on the crushed side was 40% or less of that on the normal side immediately after crushing. How does the distance between the toes recover? Starting at ⁇ 16 days, the drug-treated group tended to have a significantly faster recovery compared to the control group from about 24 days to the last measurement day, 30 days later. Table 9 shows the results.
  • test compound was useful as an agent for improving or treating peripheral neuropathy.
  • a protective effect on motor impairment due to rat brain cell damage and improvement by fetal brain cell transplantation is a protective effect on motor impairment due to rat brain cell damage and improvement by fetal brain cell transplantation.
  • a portion containing dobamine cells (the substantia nigra ⁇ ⁇ ventral tegment) was cut out from the brain stem of a rat fetus from day 14 to day 17 of the embryo, and after fine cutting, triscine treatment was performed. After incubation for 30 minutes, the tissue was suspended by pipetting. Next, the suspension was implanted into the caudate nucleus on the disrupted side at 5 sites each at 5 sites, for a total of 10 ⁇ (approximately 10 5 cells). The test compound of the present invention was administered i.p. or po for 14 days from the day of transplantation.
  • the rotational movement induced by the administration of methanefu X-tamine was examined with a lapse of one week, one week, two weeks, four weeks, six weeks, eight weeks, etc., after transplantation and drug administration.
  • the number of rotations was counted six times every 10 minutes after the methanephthaline administration for the first minute, and the total number of rotations per minute was calculated.
  • the test compounds were On the test day, the number of rotations was clearly reduced as compared with the control, indicating that the test compound is useful as an agent for improving or treating central nervous system disorders.
  • mice Male BalbC 7-week-old mice were trained in a maze so that they ran straight from the starting point to a safety area three times in a T-maze three times a week beforehand. Thereafter, methylmercury chloride (hereinafter referred to as MMC) was orally administered at 6 mg kg / day to 8-week-old mice for 6 days. As a control group, there was a group of mice to which 0.1 ml of saline was administered daily. After the end of MMC administration, the compound of the present invention was orally or intraperitoneally administered for 10 days from the next day.
  • MMC methylmercury chloride
  • the maze learning was restarted in the T-type maze on the 6th day of drug administration, that is, on the 12th day from the start of the experiment, and the running behavior of the mice was observed.
  • day 10 day 21
  • day 1 day 1 (on the same day) after resumption
  • the number of mice that were tested in the ⁇ -type maze was used as the denominator.
  • the number of mice that reached the standard one that traveled to the safety area within 5 seconds
  • the number of cases decreased due to death from MMC poisoning.
  • the compound of the present invention was found to have mouse learning, memory improvement and recovery effects.
  • the acute toxicity of the compound according to the present invention was examined by the following method.
  • mice 4 to 6 male ddy 5-week-old mice were used as a group.
  • Compounds were dissolved or suspended in saline and administered orally (P.O.) or intraperitoneally (ip).-24 hours after administration, toxicity was determined. Table 10 shows the results.
  • the compound of the general formula (I) according to the present invention has a It has an accelerating effect on the proliferation of lineage cells and the formation and elongation of neurites, and also has a nerve regeneration effect, motor function recovery effect, and learning, memory, improvement and recovery effects in neuropathy rats and mice.
  • it can be suitably used for improvement and treatment of patients with nervous system diseases such as peripheral nervous system disorders, central nervous system disorders and dementia.
  • nervous system diseases such as peripheral nervous system disorders, central nervous system disorders and dementia.
  • It is also expected to be suitably used for recovery, improvement, and treatment of nervous system diseases caused by disorders of nerve tissue and cells involved in sensory and autonomic functions.
  • the compounds of the present invention were found to have a biological activity equal to or higher than that of the control isaxonine. Further, the toxicity of the compound of the present invention is generally weak as shown in Experimental Example 5 and Table 10. As described above, the compound of the present invention is generally considered to be a highly safe drug having high activity and low toxicity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à un composé de pyrimidine représenté par la formule générale (I), à des sels pharmaceutiquement acceptables de ce composé, ainsi qu'à un médicament contenant un tel composé en vue de servir dans le traitement de maladies du système nerveux. Dans la formule (I), X représente un amino substitué ou cyclique et Y représente un amino substitué ou un carbonyle substitué. Ces composés ont une action promouvant la croissance des cellules nerveuses ainsi que la formation et l'extension des axones, de sorte qu'ils peuvent servir à traiter diverses maladies neurales.
PCT/JP1991/000898 1990-07-03 1991-07-03 Compose de pyrimidine et sel pharmaceutiquement acceptable de ce compose WO1992000970A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US07/836,283 US5358945A (en) 1990-07-03 1991-07-03 Pyrimidine compound and pharmaceutically acceptable salts thereof
DE69120221T DE69120221T2 (de) 1990-07-03 1991-07-03 Pyrimidin-verbindung und ihr pharmazeutisch annehmbares salz
KR1019920700487A KR950007756B1 (ko) 1990-07-03 1991-07-03 피리미딘 화합물 및 그의 약학적으로 허용되는 염류
EP91911732A EP0489925B1 (fr) 1990-07-03 1991-07-03 Compose de pyrimidine et sel pharmaceutiquement acceptable de ce compose

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP17607790 1990-07-03
JP2/176077 1990-07-03

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WO1992000970A1 true WO1992000970A1 (fr) 1992-01-23

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EP (1) EP0489925B1 (fr)
KR (1) KR950007756B1 (fr)
AT (1) ATE139117T1 (fr)
CA (1) CA2065443A1 (fr)
DE (1) DE69120221T2 (fr)
WO (1) WO1992000970A1 (fr)

Cited By (1)

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US7101869B2 (en) 1999-11-30 2006-09-05 Pfizer Inc. 2,4-diaminopyrimidine compounds useful as immunosuppressants

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AP3907A (en) 2011-09-27 2016-11-23 Novartis Ag 3-Pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
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US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
PE20151939A1 (es) 2013-03-14 2016-01-08 Novartis Ag 3-pirimidin-4-il-oxazolidin-2-onas como inhibidores de idh mutante

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EP0489925B1 (fr) 1996-06-12
CA2065443A1 (fr) 1992-01-04
DE69120221T2 (de) 1996-11-21
US5358945A (en) 1994-10-25
KR950007756B1 (ko) 1995-07-14
ATE139117T1 (de) 1996-06-15
EP0489925A4 (en) 1993-01-20
DE69120221D1 (de) 1996-07-18
KR927002350A (ko) 1992-09-03
EP0489925A1 (fr) 1992-06-17

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